An agonistic anti-DR5 monoclonal antibody

Apoptosis is a normal cellular process critical to the removal of damaged, mutated, or superfluous cells. Often mutations in cancer cells result in aberrations to the apoptotic-signaling pathway, leading to uncontrolled cell growth and tumor formation.

Apoptosis may be induced by the activation of a family of surface receptors called death receptors (DR). One of these receptors is death receptor 5 (DR5). The activation of DR5 on tumor cells by agonistic antibodies may be an effective approach to inducing apoptosis in cancer cells.

Novartis Oncology is currently developing an anti-DR5 mAb, LBY135. LBY135 binds to DR5 and triggers apoptosis by activating the caspase pathway.

LBY135 is now being investigated in Phase I clinical trials in solid tumors.

A fully human,* antagonistic anti-CD40 monoclonal antibody with a dual mechanism of action

CD40 is a cell-surface receptor that plays pivotal roles in immune responses, as well as cell growth and survival signaling, through its activation by CD40 ligand. CD40 is commonly over expressed and activated in B-cell malignancies. Some of these B-cell malignancies, such as multiple myeloma and chronic lymphocytic leukemia (CLL), often develop resistance to cytotoxic agents used in standard treatment regimens. Thus, CD40 targeted agents have great potential as anticancer therapeutics.

HCD122 is a fully human mAb with 2 potential mechanisms of anticancer activity:

• Blocking the interaction of CD40 and its ligand on malignant cells, thereby inhibiting proliferation and inducing apoptosis of malignant cells
• Mediating ADCC, whereby immune effector cells destroy HCD122-bound CD40-expressing malignant cells.

Antitumor activity of HCD122 has been demonstrated in preclinical animal models.

HCD122 is now being investigated in Phase I clinical trials in CLL and multiple myeloma.

An oral, multitargeted receptor TKI

TKI258 is an oral TKI that has been demonstrated preclinically to target multiple growth-factor receptors:

• Fibroblast growth-factor receptor, which plays a role in cell development, angiogenesis, and tumorigenesis
• VEGFR, which mediates angiogenesis and lymphangiogenesis
• PDGFR, which is associated with tumor progression and metastasis
• KIT, a receptor that induces cell proliferation and inhibits apoptosis
• Fms-like tyrosine kinase 3 (FLT-3), which mediates cell growth and survival and inhibits tumor-cell differentiation and apoptosis.

Due to its unique target profile, TKI258 exhibits both antitumor and antiangiogenic activity, and induces apoptosis in preclinical models of various cancers (acute myelogenous leukemia (AML), multiple myeloma, prostate, breast, colon, lung, and ovarian).

Due to its unique target profile, TKI258 exhibits both antitumor and antiangiogenic activity, and induces apoptosis in preclinical models of various cancers (AML, multiple myeloma, prostate, breast, colon, lung, and ovarian).

TKI258 is currently in Phase I clinical trials in AML, multiple myeloma, and malignant melanoma.

TKI258 is now being investigated in Phase I clinical trials in AML, multiple myeloma, and malignant melanoma.

An oral, highly selective, and potent RAF and VEGFR kinase inhibitor

Raf is a key component of the Ras-Raf-MEK-ERK signal transduction pathway, which controls cell proliferation, differentiation, and apoptosis in mammalian cells and may play a key role in many cancers. Mutation and overexpression of components of the pathway are common in various cancers. There are three isoforms of Raf: A-Raf, B-Raf, and C-Raf16. Activating mutations of B-Raf have been identified in multiple cancers, especially malignant melanoma (B-Raf V660E). In addition, Ras is often mutated to an oncogenic form in many solid tumors and hematologic malignancies.

RAF265 is a potent inhibitor of Raf with a highly selective profile. Preclinical research has shown that RAF265 inhibits all 3 isoforms of Raf, as well as mutant B-Raf, with high potency. In addition, RAF265 has antiangiogenic activity through inhibition of VEGFR-2. Antitumor activity of RAF265 has been seen in preclinical xenograft models.

RAF265 is now being investigated in Phase I clinical trials in malignant melanoma.

Inhibiting tumor proliferation and survival by blocking the phosphatidylinositol-3-kinase (PI3K) pathway

PI3Ks are key players in an intracellular signaling network, the so-called PI3K PDK PKB pathway, which regulates cell proliferation, growth, survival, and apoptosis. A substantial number of epidemiological and experimental studies support an important role for PI3Ks in the biology of human cancer. The activation of PI3Ks and downstream effectors, including PKB (AKT) and mTOR, have been validated as an essential step for the initiation and maintenance of the tumorigenic phenotype.

Activation of the PI3K-PDK1-PKB pathway, via the loss of PTEN or the over expression of some receptor tyrosine kinases (EGFR, HER-2), has been implicated in poor prognosis and survival in a number of tumor types, including breast, prostate, lung, glioblastoma, melanoma, bladder, endometrial carcinoma and lymphatic tumors.

Inhibition of the PI3K pathway could result in

• Increased apoptosis
• Decreased cell proliferation
• Decreased growth
• Decreased cell survival.

Novartis Oncology is currently developing a novel oral PI3K inhibitor, BEZ235. In preclinical studies, BEZ235 showed high target specificity and demonstrated antiproliferative activity against tumor cell lines in animal models of cancer.

BEZ235 is now being investigated in Phase I clinical trials in solid tumors.

Inhibiting cell proliferation and angiogenesis by blocking multiple tyrosine kinase receptors

The role of EGFR, HER-2, and VEGFR in the progression of cancer is well established. Aberrant EGFR and HER-2 expression is associated with advanced disease and poor patient prognosis in many tumor types, including breast, lung, ovarian, prostate, glioma, and gastric, as well as squamous carcinoma of the head and neck.18 Antiangiogenic therapies via inhibition of VEGFR have shown significant clinical benefit.19 Combination EGFR/HER-2 and VEGFR treatment strategies have the potential to improve antitumor efficacy compared with either treatment alone and may even broaden application possibilities.

Novartis Oncology is actively developing agents that block simultaneous signaling by targeting several different protein kinases and other proteins involved in cell regulation.

AEE788 is an oral, multiple-receptor TKI of EGFR, HER-2, and VEGFR.

In preclinical studies, AEE788 showed high target specificity and demonstrated antiproliferative activity against tumor cell lines in animal models of cancer. In these studies, AEE788 also exhibited direct antiangiogenic activity.

AEE788 is now being investigated in Phase I clinical development.

Potent pan-DAC inhibitor - targeting epigenetic and multiple oncogenic pathways

Novartis Oncology is investigating the pan-DAC inhibitor LBH589. Pan - DAC inhibitors have been shown to have multiple effects in tumor cell lines: decreased oncoprotein expression (e.g., Bcr-Abl, HER-2), decreased angiogenesis, induction of apoptosis, induction of cell-cycle arrest, and decreased tumor cell motility and invasion.

By interfering with the hallmarks of cancer, pan-DAC inhibitors have potential in many hematologic and solid malignancies, including lymphomas, chronic myeloid leukemia, multiple myeloma, breast cancer, and prostate cancer.

LBH589 was identified as a potent DAC inhibitor, which induced cell death of tumor cell lines but not normal cells. LBH589 has a long half-life in cells, leading to prolonged acetylation. In Phase I trials, clinical activity has been seen with LBH589 in cutaneous T-cell lymphoma (CTCL). Preclinically, LBH589 has also been shown to overcome resistance to kinase inhibition in tumor cell lines. Furthermore, preclinical synergy in combination with chemotherapy and other agents has been shown.

LBH589 is now being investigated in Phase II clinical trials in CTCL, chronic myeloid leukemia, and multiple myeloma.

PKC412

Inhibiting multiple signal transduction pathways

Protein kinase C412 (Midostaurin) is an oral multitargeted kinase inhibitor. It potently inhibits the FLT-3 receptor tyrosine kinase, which is mutated in approximately one third of acute myelogenous leukemia (AML) patients, and is implicated in poor prognosis. It also inhibits multiple other molecular targets thought to be important for the pathogenesis of AML. These targets include VEGFR-2, platelet-derived growth- factor receptor (PDGFR), c-KIT, and the Pgp-mediated multidrug resistance gene MDR.

In a Phase IB study of Midostaurin in combination with daunorubicin and cytarabine, 11 of 12 (92%) patients with newly diagnosed FLT-3 mutated AML had a complete response.

In addition to the above targets, Midostaurin inhibits multiple isoforms of the serine/ threonine PKC. In p reclinical studies, Midostaurin showed broad antiproliferative activity against various tumor cell lines, including those that were resistant to several other chemotherapeutic agents.

Midostaurin is now being investigated in Phase III trials in AML.

A potent oral topoisomerase I inhibitor

Topoisomerases are enzymes responsible for facilitating DNA replication. Topoisomerase I inhibitors have an established role in the management of CRC, small-cell lung cancer, ovarian cancer, and cervical cancer. Gimatecan is an oral topoisomerase I inhibitor that preclinical studies have shown is not a substrate for multidrug-resistance pumps.

Gimatecan is now being investigated in Phase II clinical trials in solid tumors.

*Gimatecan is licensed from sigma-tau S.p.A.

Bcr-Abl tyrosine kinase inhibitor

Nilotinib is a TKI specifically designed to be the most selective inhibitor of Bcr-Abl - the definitive causative abnormality in chronic myelogenous leukemia (CML) - and its mutant forms. Nilotinib was developed to overcome imatinib resistance or intolerance. In a Phase I study, hematologic and cytogenetic responses were seen with nilotinib in patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) CML in chronic phase, accelerated phase, and myeloid and lymphoid blast crises.

Built on the vast knowledge and experience Novartis acquired during the development of imatinib, nilotinib has been specifically designed to be a significantly more selective and potent inhibitor of Bcr-Abl than imatinib. Nilotinib has been found, in vitro, to be active against 32 of the 33 most common Bcr-Abl mutations known to cause imatinib resistance.

Registration and Phase III studies are underway to determine the safety, efficacy, pharmacokinetic profile, and biologic activity of nilotinib in adult Ph+ CML patients in blast crisis, accelerated, or chronic phase, who are either intolerant of or resistant to imatinib.

Additionally, nilotinib is now being investigated in Phase II and III trials in Ph+ CML. Ongoing trials include ENACT (Expanding Nilotinib Access in Clinical Trials), a global expanded-access program created to increase access to nilotinib for eligible patients who are resistant to or intolerant of imatinib. A Phase II study is also investigating nilotinib in c-KIT-positive gastrointestinal stromal tumor (GIST).

Pasireotide

A multiligand somatostatin analogue

Somatostatin is a peptide hormone expressed in many tissues throughout the body. It regulates the release of hormones such as growth hormone (GH), glucagons, insulin, gastrin, secretin, and thyroid-stimulating hormone. Somatostatin inhibitors block GH release.

The potential of somatostatin analogues as cancer therapies has recently been explored following demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo.

Pasireotide is the next generation in somatostatin analogues. This multiligand-targeting agent is currently in late Phase II development for acromegaly and gastroentero pancreatic neuroendocrine tumors (GEP/NET), and is entering Phase III development for Cushing's disease.

Pasireotide exhibits a broad spectrum of somatostatin receptor activation. Compared with octreotide in vitro, pasireotide has far higher binding affinity for sst-1, sst-3, and sst-5 receptors (30, 5, and 40 times, respectively), and a comparable affinity for sst-2 receptors.

Everolimus

Blocking mTOR - a central regulator of cancer-cell growth and metabolism

The mammalian target of rapamycin (mTOR) is an intracellular protein that acts as a central regulator of multiple signaling pathways (IGF, EGF, PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation, survival, and angiogenesis in cancer. mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers.

RAD001 is an oral kinase inhibitor that specifically blocks the mTOR protein. By inhibiting cell proliferation, cellular bioenergetics, and angiogenesis, RAD001 may provide clinical benefit to patients with cancer.

RAD001 may have antiangiogenic activity due to inhibition of tumoral VEGF production and inhibition of pericyte and endothelial cell proliferation.

RAD001 is now being investigated in Phase I to III clinical trials in multiple tumor types, including neuroendocrine tumors, renal cell carcinoma, and colorectal, lung, and breast cancers.

Inducing cell death through microtubule stabilization

Interference with microtubule formation and function, which is required for cell division and also endothelial-cell function, is an established antitumor strategy where agents stabilize and promote the formation of microtubules, which causes cell-cycle arrest and ultimately tumor-cell death. However, current agents such as taxanes (including paclitaxel and docetaxel) are associated with toxicities that are often treatment- and schedule-limiting, and have limited utility in treating multidrug-resistant tumor cells.

Patupilone belongs to a new class of microtubule stabilizers, the epothilones, which may have potential advantages over other microtubule stabilizers. Preclinical studies have shown that Patupilone is more potent than paclitaxel in cell lines; is a poor/nonsubstrate for the major drug efflux pumps; and is active in taxane-resistant tumors, such as brain tumors.

Preliminary clinical data suggest a low incidence of neutropenia and alopecia, as well as predictable and generally manageable diarrhea. Clinical activity has been seen in multiple solid tumors such as ovarian, colorectal cancer (CRC), non-small-cell lung cancer (NSCLC) - including patients with brain metastases; prostate, breast, gastric, and renal cancers; melanoma; and carcinoid tumors.

Patupilone is now being investigated in Phase III clinical trials in ovarian cancer.

Bcr-Abl tyrosine kinase inhibitor

Nilotinib is a TKI specifically designed to be the most selective inhibitor of Bcr-Abl - the definitive causative abnormality in chronic myelogenous leukemia (CML) - and its mutant forms. Nilotinib was developed to overcome imatinib resistance or intolerance. In a Phase I study, hematologic and cytogenetic responses were seen with nilotinib in patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) CML in chronic phase, accelerated phase, and myeloid and lymphoid blast crises.

Built on the vast knowledge and experience Novartis acquired during the development of imatinib, nilotinib has been specifically designed to be a significantly more selective and potent inhibitor of Bcr-Abl than imatinib. Nilotinib has been found, in vitro, to be active against 32 of the 33 most common Bcr-Abl mutations known to cause imatinib resistance.

Phase II study has been completed and Phase III trials are ongoing.

Ongoing trials include ENACT (Expanding Nilotinib Access in Clinical Trials), a global expanded-access program created to increase access to nilotinib for eligible patients who are resistant to or intolerant of imatinib. A Phase II study is also investigating nilotinib in c-KIT-positive gastrointestinal stromal tumor (GIST).

The compound NILOTINIB described in this site has been approved in a number of countries for Ph+ CML; it has not been approved in any countries for KIT+ GIST. If NILOTINIB has not yet been approved in your country, there is no guarantee that NILOTINIB will become commercially available.